A comprehensive toxicity evaluation in rats after long-term oral Gelsemium elegans exposure

Zuo, Meng-Ting; Yong, Wu; Wang, Ziyuan; Wang, Na; Huang, Si-Juan; Yu, Hui; Zhao, Xia; Huang, Chong-Yin; Liu, Zhao‐Ying

doi:10.1016/j.biopha.2021.111284

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…In addition, previous studies have proven that removal of extracellular calcium could decrease neuronal degeneration induced by excitotoxicity [ 45 ]. Ca 2+ will also affect the release of neurotransmitters [ 46 ], which is consistent with our hypothesis that the toxicity of Gelsemium derived from the imbalance between neurotransmitters [ 47 ]. As for the MAPK signaling pathway, this is another important pathway enriched by KEGG.…”

Section: Discussionsupporting

confidence: 88%

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

Huang

Zuo

et al. 2023

Metabolites

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Gelsemium is a medicinal plant that has been used to treat various diseases, but it is also well-known for its high toxicity. Complex alkaloids are considered the main poisonous components in Gelsemium. However, the toxic mechanism of Gelsemium remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of Gelsemium toxicity. The alkaloid compounds and candidate targets of Gelsemium, as well as related targets of excitotoxicity, were collected from public databases. The crucial targets were determined by constructing a protein–protein interaction (PPI) network. Subsequently, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the bioprocesses and signaling pathways involved in the excitotoxicity corresponding to alkaloids in Gelsemium. Then, the binding affinity between the main poisonous alkaloids and key targets was verified by molecular docking. Finally, animal experiments were conducted to further evaluate the potential mechanisms of Gelsemium toxicity. A total of 85 alkaloids in Gelsemium associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of Gelsemium was mainly related to the protein phosphorylation reaction and plasma membrane function. There were also 164 pathways involved in the toxic mechanism, such as the calcium signaling pathway and MAPK signaling pathway. Molecular docking showed that alkaloids have high affinity with core targets, including MAPK3, SRC, MAPK1, NMDAR2B and NMDAR2A. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD50 values of female and male mice were 0.071 mg·kg−1 and 0.149 mg·kg−1, respectively. Furthermore, we found that N-methyl-D-aspartic acid (NMDA), a specific NMDA receptor agonist, could significantly increase the survival rate of acute humantenirine-poisoned mice. The results also show that humantenirine could upregulate the phosphorylation level of MAPK3/1 and decrease ATP content and mitochondrial membrane potential in hippocampal tissue, while NMDA could rescue humantenirine-induced excitotoxicity by restoring the function of mitochondria. This study revealed the toxic components and potential toxic mechanism of Gelsemium. These findings provide a theoretical basis for further study of the toxic mechanism of Gelsemium and potential therapeutic strategies for Gelsemium poisoning.

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Section: Discussionsupporting

confidence: 88%

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

Huang

Zuo

et al. 2023

Metabolites

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“…It is also worth mentioning that these bioactive components were present in high levels in urine and relatively little in plasma and tissues, indicating their rapid excretion. Previous subchronic toxicity studies have shown that G. elegans does not cause accumulation damage in the organism, which is inseparable from the rapid excretion of the main toxic components [ 29 ]. Cytochrome P450 enzymes (CYP450) are widely distributed in the body and play pivotal roles in drug metabolism [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in the In Vivo Exposure Process of Multiple Components of Gelsemium elegans in Rats

Zuo

Gong

et al. 2022

Metabolites

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Asian Gelsemium elegans (G. elegans) has a wide range of pharmacological activities. However, its strong toxicity limits its potential development and application. Interestingly, there are significant gender differences in G. elegans toxicity in rats. This work aimed to elucidate the overall absorption, distribution, metabolism, and excretion (ADME) of whole G. elegans crude extract in female and male rats using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS), which facilitates determining the reasons for the gender differences in toxicity. A total of 25 absorbed bioactive components and 3 related produced metabolites were tentatively identified in female rats, while only 17 absorbed bioactive components and 3 related produced metabolites were identified in male rats. By comparison of peak intensities, most compounds were found to be more active in absorption, distribution and excretion in female rats than in male rats, which showed that female rats were more sensitive to G. elegans. This study was the first to investigate the multicomponent in vivo process of G. elegans in rats and compare the differences between sexes. It was hypothesized that differences in the absorption of gelsedine-type alkaloids were one of the main reasons for the sex differences in G. elegans toxicity.

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“…The term “vitamin B6” refers to a number of chemically related substances, the most prevalent of which being pyridoxine, which is also the substance present in commercially available vitamin supplements. The generation of neurotransmitters, amino acid metabolism, glucose metabolism, lipid metabolism, hemoglobin synthesis and function, and gene expression are just a few of the body’s enzymatic processes that require VB6 [ 161 ]. In addition, it plays a role in the biosynthesis of fatty acids, the catabolization of different compounds that are used as storage in both animals and plants, as well as the biosynthesis of plant hormones, and organelle-specific substances like chlorophyll [ 162 ].…”

Section: The Effects Of Pyridoxine/vb6 Bioavailability Dose and Effic...mentioning

confidence: 99%

“…A subset of women who use oral contraceptives had reduced levels of pyridoxine phosphate [ 169 ]. Phenobarbital and phenytoin blood levels may drop in response to high pyridoxine doses [ 161 ]. Some authors assume that the accumulation of VB6 takes place in the liver [ 170 ].…”

Section: The Effects Of Pyridoxine/vb6 Bioavailability Dose and Effic...mentioning

confidence: 99%

B Vitamins, Glucoronolactone and the Immune System: Bioavailability, Doses and Efficiency

Munteanu,

Schwartz

2023

Nutrients

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The present review deals with two main ingredients of energy/power drinks: B vitamins and glucuronolactone and their possible effect on the immune system. There is a strong relationship between the recommended daily dose of selected B vitamins and a functional immune system. Regarding specific B vitamins: (1) Riboflavin is necessary for the optimization of reactive oxygen species (ROS) in the fight against bacterial infections caused by Staphylococcus aureus and Listeria monocytogenes. (2) Niacin administered within normal doses to obese rats can change the phenotype of skeletal fibers, and thereby affect muscle metabolism. This metabolic phenotype induced by niacin treatment is also confirmed by stimulation of the expression of genes involved in the metabolism of free fatty acids (FFAs) and oxidative phosphorylation at this level. (3) Vitamin B5 effects depend primarily on the dose, thus large doses can cause diarrhea or functional disorders of the digestive tract whereas normal levels are effective in wound healing, liver detoxification, and joint health support. (4) High vitamin B6 concentrations (>2000 mg per day) have been shown to exert a significant negative impact on the dorsal root ganglia. Whereas, at doses of approximately 70 ng/mL, sensory symptoms were reported in 80% of cases. (5) Chronic increases in vitamin B12 have been associated with the increased incidence of solid cancers. Additionally, glucuronolactone, whose effects are not well known, represents a controversial compound. (6) Supplementing with D-glucarates, such as glucuronolactone, may help the body’s natural defense system function better to inhibit different tumor promoters and carcinogens and their consequences. Cumulatively, the present review aims to evaluate the relationship between the selected B vitamins group, glucuronolactone, and the immune system and their associations to bioavailability, doses, and efficiency.

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A comprehensive toxicity evaluation in rats after long-term oral Gelsemium elegans exposure

Cited by 7 publications

References 48 publications

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

Sex Differences in the In Vivo Exposure Process of Multiple Components of Gelsemium elegans in Rats

B Vitamins, Glucoronolactone and the Immune System: Bioavailability, Doses and Efficiency

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